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VHL down-regulation and differential localization as mechanisms in tumorigenesis

  1. Author:
    Shiao, Y. H.
    Forsti, A.
    Egevad, L.
    Anderson, L. M.
    Lindblad, P.
    Hemminki, K.

  2. Author Address

    NCI, Comparat Carcinogenesis Lab, NIH, Bldg 538,Room 205, Frederick, MD 21702 USA NCI, Comparat Carcinogenesis Lab, NIH, Frederick, MD 21702 USA Karolinska Inst, Novum, Dept Biosci, Huddinge, Sweden German Canc Res Ctr, D-6900 Heidelberg, Germany Karolinska Hosp, Dept Pathol & Cytol, S-10401 Stockholm, Sweden Sundsvall Hosp, Dept Urol, Sundsvall, Sweden Shiao YH NCI, Comparat Carcinogenesis Lab, NIH, Bldg 538,Room 205, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Kidney International
    1. 64
    2. 5
    3. Pages: 1671-1674
  4. Type of Article: Article
  1. Abstract:

    Background. The von Hippel-Lindau (VHL) gene has been widely analyzed in many tumors. Early studies in animal tumors suggest that changes in VHL protein level and localization may be also important in tumorigenesis. In this study, we determined the role of VHL protein in human renal cell carcinomas. Methods. Seventy-five human renal cell carcinomas, predominantly of clear cell type (60 of 75), were examined for VHL protein by immunohistochemistry. The level and pattern of protein expression were then compared to VHL mutations and tumor characteristics. Results. An apparent decline of VHL level (positive in <50% of tumor cells) was observed in 49 (65%) tumors, a change more frequent than VHL mutations (28 of 75) (37%). In tumors, VHL was localized to the cytoplasm and/or the cell membrane. The occurrence of a predominantly membranous signal was significantly associated with missense mutations (9 of 14 tumors with missense mutations versus 14 of 61 tumors with no or nonmissense mutations, P = 0.0025) and tumor stage (23 of 60 tumors with stage TI versus 0 of 15 tumors with TII and TIII, P = 0.0034). Conclusion. This study provides the first evidence of the role of VHL protein level and intracellular localization in tumorigenesis in humans.

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